Vascular disease and cardiovascular risk factors (diabetes, hyperlipidemia and hypertension) are strongly associated with Alzheimer's disease (AD) yet the mechanisms by which they lead to AD remain unknown. It is now well-recognized that vascular dysfunction leading to cerebral hypo perfusion and impaired blood brain barrier function occur early in AD and has a central role in early pathophysiology. Critical obstacles in AD research include the lack of knowledge of how cardiovascular risk factors contribute to AD or modulate A injury, and the lack of a human tissue model to study early vascular disease in AD. Our preliminary data show the feasibility of using ex-vivo leptomeningeal arterioles isolated by rapid autopsy from organ donors to study micro vascular response to A and cardiovascular risk factors. Our overall goal is to identify key mechanisms underlying A -induced micro vascular injury and systematically study how cardiovascular risk factors modulate A effects on endothelial function, oxidative stress and vascular inflammation. We hypothesize that A induces endothelial dysfunction and vascular inflammation through oxidative stress and activation of receptor for advanced glycation end products (RAGE) and nuclear factor kappa B (NF-KB) signaling, and hyperglycemia (HG) and palmitic acid (PA) will exacerbate A vascular toxicity by modulating these pathways in cerebral and peripheral adipose arterioles. In Aim 1 we will quantify the effects of exposure to A HG or PA) on vascular function of leptomeningeal arterioles taken from AD, mild cognitive impairment (MCI) and cognitively normal (CN) subjects while identifying key inflammatory and oxidative stress signaling mechanisms modulating the responses. In Aim 2 we will establish the validity of peripheral adipose arterioles as a practical human surrogate model to study central brain arteriole response to AD stressors by comparing vascular, oxidative stress and inflammatory signaling responses in cadaver and living subject adipose arterioles exposed to A HG or PA to cadaver leptomeningeal arterioles. The proposal will provide novel mechanistic insights on the critical interaction and modulating effects of cardiovascular risk factors and A on human micro vessels while comparing vascular responses to known AD stressors among AD, MCI and CN subjects. The validation of adipose arterioles as an acceptable surrogate to brain micro vessels will provide a practical human model to study mechanisms and treatments of early vascular injury from AD stressors.